The pathology of traumatic brain injury in experimental models includes acute inflammatory reaction, blood brain barrier disruption, hemorrhage, demyelination, axonal transection and chronically with axonal neuronal loss and gliosis. Stem cell (SC) therapy is a potential treatment either as replacement therapy or via paracrine effect with release of growth factors and anti-inflammatory cytokines for TBI injury. Experimental studies in rodent models of TBI have been limited and usually a single dose of cells is administered within 24 to 72 hours after experimental injury. The optimal timing and dose of cell delivery to maximize functional recovery and transplantation survival during the acute inflammatory and edematous phase of damage is unknown. We evaluated the natural history of control cortical impact (CCI) to induce TBI in the rat brain by serial MRI, molecular biological and histological analysis. Following TBI, inflammatory macrophages (M1) predominate over anti-inflammatory macrophages (M2). We investigated the temporal profile of M1/M2 phenotypes in macrophages and microglia after CCI and examined the post-injury M1/M2 time course in brain. The macrophage/microglial response peaked at 5 to 7 days post-TBI, with characteristics of mixed populations of M1 and M2 phenotypes with a peak of M2-associated staining occurred at 5 days post-TBI. Chemokine analysis by multiplex assay showed statistically significant increases in macrophage inflammatory protein-1a and Mouse keratinocyte-derived cytokine on the ipsilateral side within the first 24 hours after injury relative to control and to the contralateral side. The macrophage/microglial response to histologically severe CCI in the female rat is maximal between days 3 and 7. The brain microenvironment has elements of both pro- and anti-inflammatory responses within the first week after traumatic injury, rather than one that is clearly skewed more towards an M1 versus M2 phenotype. This mixed pattern has relevance to translation of results to clinical populations as to when to possibly institute treatment to down-regulate inflammation or stimulate repair process. A spectrum of macrophage and microglial phenotypes exists after CCI, likely reflecting a complex inflammatory response in which the cells may adjust their functions based upon the post-traumatic milieu. We also reported that the efficacy of multiple intravenous or intracardiac administrations of rat mesenchymal stromal cells or human mesenchymal stromal cells in female rats after controlled cortical impact by in vivo MRI, neurobehavior, and histopathology evaluation. Neither intravenous nor intracardiac administration of mesenchymal stromal cells derived from either rats or humans improved MRI measures of lesion volume or neurobehavioral outcome compared to saline treatment. Few mesenchymal stromal cells (<0.0005% of injected dose) were found within 3 days of last dosage at the site of injury after either delivery route, with no mesenchymal stromal cells being detectable in brain at 30 or 56 days post-injury. These findings suggest that non-autologous mesenchymal stromal cells therapy via intravenous or intracardiac administration is not a promising treatment after focal contusion traumatic brain injury in this female rodent model.